Tamoxifen is a useful therapy for some but not all breast cancer patients with estrogen receptor positive (ER+) tumors. Second line hormonal therapies have limited effectiveness in patients who have failed following a response to tamoxifen treatment for metastatic disease or relapsed after receiving adjuvant tamoxifen therapy. A better understanding of the mechanisms responsible for acquired tamoxifen resistance should provide the conceptual basis for additions or modifications to current treatment regimens that will extend or restore sensitivity or prolong the therapeutic effect of tamoxifen and other selective estrogen receptor response modifiers (SERMS). Recent clinical data suggests that the extent of neoangiogenesis ongoing within a patient's tumor is inversely related to the extent derived from adjuvant hormonal therapy. Our own preliminary and published data indicate that paracrine effects of angiogenic growth factor production by ER+ human breast tumor cells growing as xenografts in athymic nude mice can reduce the effectiveness of tamoxifen as a cytostatic or cytotoxic agent. The studies proposed in this project are designed to use these cell lines as model system to identify the molecular mechanisms responsible for this effect. In aims 1 and 2, ER+ breast tumor cells engineered to over-express the165 amino acid form of VEGF-A in a tetracycline regulated manner will be used to determine how angiogenic growth factor product alters the balance of cell proliferation and cell death within xenografts excised from tamoxifen treated mice. In aim 3 we will determine whether angiogenic growth factor over-expression. In aim 4, we will test the ability of novel VEGFR antagonists that are now in early phase clinical trials to restore tamoxifen sensitivity or prevent the development of new tumors when used in combination with tamoxifen in a NMU carcinogen induced rat mammary carcinoma model will also be explored. In aim 5, we will perform a pilot clinical trial to determine if addition of a VEGFR antagonist to the treatment regimen can restore tamoxifen sensitivity to patients with recurrent metastatic breast cancer who either initially responded to tamoxifen treatment or relapsed following adjuvant therapy.